Clinical trial of GLP-1 agonist Lixisenatide to treat early Parkinson’s Disease

Parkinson's disease (PD) is a progressive neurological disorder causing tremors, stiffness, slow movement, and balance problems. While there's no cure, researchers are tirelessly exploring new avenues to slow down its progression. A recent clinical trial has shed light on the potential of a diabetes medication, lixisenatide, to reduce the worsening of motor symptoms in early Parkinson's.

Parkinson's disease develops when the brain cells responsible for producing dopamine, a crucial chemical messenger for movement, start to die. The reasons behind this cell death are not fully understood, but it's likely a combination of genetics and environmental factors. Symptoms typically appear gradually and worsen over time. While there's no cure, a range of therapies can help manage the condition.

The mainstay of Parkinson's treatment focuses on medications and therapies that aim to increase dopamine levels or compensate for its decline, alongside deep brain stimulation (DBS) for selected patients. Common medications include:

• Levodopa: Remains the most effective treatment, but long-term use can cause side effects.
• Dopamine agonists: Mimic dopamine's action but with potential side effects like nausea and sleepiness.
• MAO-B and COMT inhibitors: Prolong dopamine's effect in the brain.
• Others: Less commonly used options include amantadine and anticholinergics.

Therapies like physical, occupational, and speech therapy are invaluable for maintaining function and addressing specific challenges.

GLP-1 receptor agonists, like lixisenatide (and ozempic), are primarily known for treating type 2 diabetes, and more recently, obesity. However, exciting early research suggests they might also protect and restore brain cells affected by Parkinson's.  This class of drugs has shown promise in animal models, prompting investigation into their potential for humans.

The phase 2 LIXIPARK trial, published in the New England Journal of Medicine, was a major step in evaluating lixisenatide for early Parkinson's disease in a double-blind, randomized, placebo-controlled trial. There were 156 participants (40 to 75 years old) with recently diagnosed Parkinson's who were randomly assigned to either lixisenatide injections or placebo for 12 months. Importantly, they were already receiving standard Parkinson's medications. In addition, those with diabetes were excluded. The primary focus was measuring changes in motor disability using a specialized scale (MDS-UPDRS part III). At the start of the trial, the baseline score was ~15 for both groups.

After 12 months, the lixisenatide group showed a slight improvement (-0.04 points) on the MDS-UPDRS part III, while the placebo group's score worsened (3.04 points). This difference of 3.08 points (95% CI, 0.86 to 5.30; P=0.007) was statistically significant. After the 12 month treatment period, patients were followed for an additional two months without any lixisenatide. The average MDS-UPDRS score in the lixisenatide group was 17.7 (95% CI, 15.7 to 19.7) compared to 20.6 (95% CI, 18.5 to 22.8) in the placebo group after the two months. This indicates that the lixisenatide group maintained better motor function compared to the control group, although both groups worsened during this washout period (in which lixisenatide was no longer administered to the treatment group).

The results were both surprising and encouraging, but some caution is needed when evaluating the findings. First, the differences and changes in motor scores attributable to the lixsenatide treatment were relatively modest, and the treatment period was short (12 months). Whether this translates into a meaningful difference in everyday life for patients needs further exploration. Second, the trial only involved people with early Parkinson's; the effect on later stages is unknown. Finally, larger and longer studies are essential to confirm these results and fully assess lixisenatide's safety and effectiveness over time.

A big question is the mechanism of action. One possibility is that lixisenatide is exerting its potentially beneficial effects by ameliorating type 2 diabetes and/or obesity. As mentioned above, diabetic patients were excluded from the trial, and so it seems less likely that the mechanism of action is via treating diabetes. Another possibility is that the GLP-1 agonist is acting directly on brain targets. It is known that GLP-1 receptors are found in the brain, and pre-clinical studies in animal models have shown that GLP-1 "displays critical roles in neuroprotection by activating the GLP-1 receptor signaling pathways. GLP-1 enhances learning and memory in the hippocampus, promotes neurogenesis, decreases inflammation and apoptosis, modulates reward behavior, and reduces food intake" (link). It should be noted that both GLP-1 and the GLP-1 agonists are able to cross the blood-brain barrier.